Traditionally, analgesics have fallen into two broad categories. Simple, non-narcotic analgesics, such as aspirin, which appear to work by inhibition of prostaglandin synthetase, are effective against pain of integumental origin such as headache and muscle aches, but are often ineffective in controlling deeper, more intense pain. Furthermore, they may cause undesirable side effects even at therapeutic dosages. The most common of these side effects is a propensity to induce dyspepsia and gastrointestinal bleeding. At higher dosages, the salicylates may have toxic effects on the central nervous system consisting of stimulation (including convulsions) followed by depression. Headache, dizziness, mental confusion, hearing difficulties and hyperventilation may also occur. Gastrointestinal symptoms may include epigastric distress, nausea and vomiting. The narcotic analgesics appear to work through interaction with the endorphin/enkephalin receptor system of the central nervous system and are useful in controlling pain which is too intense to be controlled by the weaker, non-narcotic analgesics. However, centrally-acting narcotic analgesics have several serious undesirable side effects, including the development of physical dependence and tolerance, sedation, respiratory depression, hypotension, increase in cerebrospinal fluid pressure, nausea, vomiting and constipation. In some patients, particularly the chronically ill, the narcotic side effects make it impossible to administer dosages sufficient to adequately control pain over the required time period.
This invention combines capsaicin or a capsaicin analog with a drug from the class of non-narcotic, non-steroidal anti-inflammatory, antipyretic and analgesic compounds (often referred to as "aspirin-like" drug, since the prototypical compound is aspirin), producing a synergistic increse in analgesia without a corresponding increase in side effects. The degree of analgesia produced by this combination has been found in some cases to be equivalent to that formerly obtainable only through the use of narcotics. Thus, the claimed combination makes it possible to control pain which is too severe to be adequately controlled by the non-steroidals alone, while avoiding the serious side effects and addiction potential inherent in the use of opioids.
It has been recently discovered that capsaicin, a natural product of certain species of the genus Capsicium, induces analgesia. Capsaicin (8-methyl-N-vanillyl-6Z-nonenamide) and "synthetic" capsaicin (N-vanillyl-nonanamide) are disclosed as analgesics in U.S. Pat. No. 4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicin has also been discussed in the chemical and medical literature, including Yaksh, et al, Science, 206, pp 481-483 (1979); Jancso, et al, Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp 285-288 and Holzer et al, Eur. J. Pharm. Vol. 58, pp 511-514 (1979). U.S. Pat. No. 4,238,505, Nelson, issued Dec. 9, 1980, discloses 3-hydroxyacetanilide for use in producing analgesia in animals. European Patent Application No. 0089710, LaHann, et al, published Sept. 28, 1983, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disclosed for N-vanillylsulfonamides in U.S. Pat. No. 4,401,663, Buckwalter, et al, issued Aug. 30, 1983; N-vanillylureas in European Patent Application No. 0068590, Buckwalter, et al, published Jan. 5, 1983; N-vanillylcarbamates in European Patent Application No. 0068592, Buckwalter, et al, published Jan. 5, 1983; N-[(substituted phenyl)methyl]alkynlamides in U.S. patent application Ser. No. 514,204, Janusz, et al, filed July 14, 1983; methylene substituted N-[(substituted phenyl)methyl]-alkanamides in U.S. patent application Ser. No. 514,205, Janusz, et al, filed July 14, 1983; N[(substituted phenyl)methyl]-cis-monounsaturated alkenamides in U.S. patent application Ser. No. 514,206, LaHann, et al, filed July 14, 1983; and N-[substituted phenyl)methyl]-diunsaturated amides in U.S. patent application Ser. No. 514,207, LaHann, et al, filed July 14, 1983. However, none of these references suggest in any way the desirability of concurrent administration of capsaicin or a capsaicin derivative with a non-steroidal. Further, the art suggests that it is extremely difficult to predict when a synergistic effect will be obtained from the concurrent administration of two pharmaceutical compounds which take effect through different mechanisms.
Although there are many patents which disclose analgesic and anti-inflammatory compositions containing a combination of two or more mechanistically unrelated analgesic and/or anti-inflammatory compounds, none of these compounds has a structure at all similar to that of capsaicin. See U.S. Pat. No. 4,404,210, Schmidt, issued Sept. 13, 1983; U.S. Pat. No. 4,083,981, Yamamoto, issued Apr. 11, 1978; U.S. Pat. No. 4,315,936, Capetola et al, issued Feb. 16, 1982; U.S. Pat. No. 4,379,789, Capetola et al, issued Apr. 12, 1983; and U.S. Pat. No. 4,275,059, Flora, et al, issued June 23, 1981.
Thus, based on the art, one could not have predicted that the combination of capsaicin or a capsaicin analog with a non-steroidal would result in a synergistic increase in analgesia.